New target for AD therapy identified in TNF-family protein
Periostin (shown in pink) is being used in the clinic as a marker for allergic diseases such as asthma as well as atopic dermatitis. Left image: Periostin is overexpressed in atopic dermatitis. Right image: Blocking LIGHT also blocks periostin expression. Photo by: Herro et al, courtesy of La Jolla Institute for Allergy and Immunology
A protein known as LIGHT, a member of the tumour necrosis factor (TNF) superfamily of proteins, appears to directly control hyperproliferation of keratinocytes in atopic dermatitis (AD), according to findings published in the Journal of Experimental Medicine (Jan. 18, 2018).
The LIGHT protein (homologous to lymphotoxin, exhibits inducible expression, and competes with HSV glycoprotein D for binding to HVEM, a receptor expressed on T lymphocytes) also controls the expression of periostin, a protein that contributes to the clinical features of atopic dermatitis as well as other inflammatory skin diseases, such as scleroderma, the authors note.
“Periostin is being used in the clinic as a marker for allergic diseases such as asthma as well as atopic dermatitis,” said senior author Michael Croft, PhD, in a press release from La Jolla Institute for Allergy and Immunology in La Jolla, Calif.
Dr. Croft is a professor and head in the Division of Immune Regulation at the institute.
“The fact that LIGHT acts upstream of periostin and is controlling its production really reinforces the idea that this is potentially a very good clinical target for treatment of atopic dermatitis and other inflammatory skin diseases,” he said.
When the investigators treated human epidermal keratinocytes with an antibody that blocked interactions between LIGHT and the HVEM receptor on T lymphocytes, the intervention prevented expression of periostin and limited AD symptoms.
The authors suggest that targeting this LIGHT-HVEM interaction might be a valuable treatment option for patients with severe AD.
As well, in a mouse model of AD, mice that had been engineered to not produce the LIGHT protein, or to lack the HVEM receptor, displayed minimal clinical AD symptoms, compared to control mice.
“This is the important part of the study,” lead author Rana Herro, PhD, said in the release. ”Specifically deleting the receptor in keratinocytes was enough to abrogate disease.” Dr. Herro is an instructor in Dr. Croft’s laboratory.
Further investigation showed that LIGHT stimulates the proliferation of keratinocytes and the structural remodelling of the skin. LIGHT was also found to strongly induce the expression of periostin, which animal studies have shown to be essential for skin inflammation.
“We knew that LIGHT acts as a pro-inflammatory molecule on immune cells but we were able to implicate, for the first time in a disease setting, that this molecule acts on non-immune cells like the structural cells of the skin,” said Dr. Herro. “LIGHT directly drives fibrosis, a structural remodelling process that leads to the thickening and hardening of the skin.”
“Our findings suggest that therapies that block LIGHT signalling might halt atopic dermatitis in humans and maybe even reverse disease symptoms,” Dr. Herro said.